This invention relates to pyrazoles and pyrazolopyrimidines, pharmaceutical compositions containing them, and methods of administering them to subjects in need of their corticotropin-releasing factor (CRF) antagonist activity.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g. as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache; abdominal bowel syndrome; inflammatory diseases; immune suppression; human immunodeficiency virus (HIV) infections; Alzheimer""s disease; gastrointestinal diseases; anorexia nervosa; hemorrhagic stress; drug and alcohol withdrawal symptoms; drug addiction, and fertility problems.
The compound of formula I below wherein A is Cxe2x95x90O, R1 is amino, R2 is methylthio, R3 is 2-chlorophenyl, and R4 is 2,4,6-trichlorophenyl is a commercial compound of no known utility.
The present invention relates to a compound of the formula 
and the acid addition salts thereof, wherein
A is Cxe2x95x90O or SO2, or A and R1 together with the carbons to which they are attached form pyrimidinyl or 5-pyridyl which may be substituted by R5 which is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), SH, S(O)n(C1-C6 alkyl) wherein n=0, 1 or 2, wherein said C1-C6 alkyl may be substituted by from 1 to 3 substituents R6 which is hydroxy, amino, C1-C3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(Cxe2x95x90O)CH3, fluoro, chloro, bromo or C1-C3 thioalkyl;
R1 is hydrogen, C1-C6 alkyl, amino, O(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), wherein said C1-C6 alkyl may be substituted by from 1 to 3 substituents R6 as defined above;
R2 is hydrogen, C1-C6 alkyl, hydroxy, amino, O(C1-C6 alkyl), NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), SH, S(O)n(C1-C6 alkyl) wherein n=0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(Cxe2x95x90O)(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), (Cxe2x95x90O)O(C1-C6alkyl), C1-C3alkoxy, C1-C3thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro;
R3 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 9 to 12 membered bicycloalkyl, optionally containing one to three of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or phenylmethyl, wherein each one of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 alkoxy, or trifluoromethyl, or one of cyano, nitro, amino, NH(C1-C6 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), COO(C1-C4 alkyl), CO(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), SO2NH2, NHSO2(C1-C4 alkyl), S(C1-C6 alkyl), SO2(C1-C6 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; and
R4 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl or 9 to 12-membered bicycloalkyl, optionally containing one to three of O, S or Nxe2x80x94Z wherein Z is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or phenylmethyl, wherein each of the above groups may be substituted independently by from one to three of fluoro, chloro, bromo, trifluoromethyl, C1-C6 alkyl or C1-C6 alkoxy, or one of cyano, nitro, amino, NH(C1-C6 alkyl), N(C1-C4 alkyl)(C1-C2 alkyl), COO(C1-C4 alkyl), CO(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)(C1-C2 alkyl), SO2NH2, NH2SO2(C1-C4 alkyl), S(C1-C6 alkyl), SO2(C1-C6 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl may be substituted by one or two of fluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl; provided that (1) R4 is not unsubstituted phenyl; (2) when R1 is amino, R2 is methylthio, R4 is 2,4,6-trichlorophenyl, and A is Cxe2x95x90O, then R3 is not 2-chlorophenyl; and (3) R1 and R2 are not both hydrogen.
More specific compounds of the formula I include those wherein R3 is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C1-C6 alkyl, C1-C6 alkyloxy, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, or R3 is primary, secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C4-C9 alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R6 which is hydroxy, amino, C1-C3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(Cxe2x95x90O)CH3, fluoro, chloro, bromo, or C1-C3 thioalkyl.
More specific compounds of the formula I are those wherein A is Cxe2x95x90O, those wherein R1 is amino, methylamino or dimethylamino; those wherein R2 is ethyl or methylthio and those wherein R4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl.
More specific compounds of formula I further include those wherein R3 is phenyl which may be substituted at positions 2 or 5 with one or two of methyl, C2-C6 straight-chain or branched alkyl, trifluoromethyl, fluoro, chloro, bromo or nitro, those wherein A and R1 together form a pyrimidine ring, such that the bicyclic structure formed is pyrazolo[3,4-d]pyrimidine, and R5 is substituted at the 6 position; and those wherein R3 is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C1-C6 alkyl, C1-C6 alkyloxy, SO2NH2, SO2NH(C1-C6 alkyl), or SO2N(C1-C6alkyl)2, R4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl, and R2 is methylthio, methyl or ethyl.
More specific compounds of formula I also include those wherein R3 is phenyl substituted independently with one or two of fluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C1-C6 alkyl, C1-C6 alkyloxy, SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, or R3 is primary, secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C4-C9 alkyl may contain from one to two double or triple bonds and may be substituted by from 1 to 3 substituents R6 which is hydroxy, amino, C1-C3 alkoxy, dimethylamino, diethylamino, methylamino, ethylamino, NH(Cxe2x95x90O)CH3, fluoro, chloro, bromo or C1-C3 thioalkyl; R4 is 2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl; R1 is amino, methylamino or dimethylamino; and R2 is methylthio or ethyl.
The most preferred compounds of the invention are
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone,
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-bis-trifluoromethylphenyl)methanone,
[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,
[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone, and
[5-amino-1-(4-bromo-2,6-dimethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dibromophenyl)methanone.
The invention also relates to a composition for the treatment of illnesses induced or facilitated by corticotropin releasing factor which comprises a compound of the formula I as defined above or the known compound of formula I wherein A is Cxe2x95x90O, R1 is amino, R2 is methylthio, R3 is 2-chlorophenyl, and R4 is 2,4,6-trichlorophenyl, in an amount effective in the treatment of said illnesses, and a pharmaceutically acceptable carrier, and to a composition for the treatment of inflammatory disorders, stress and anxiety related disorders including stress-induced depression and headache, abdominal bowel syndrome, immune supression, HIV infections, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, which comprises a compound of the formula I as well as the known compound, both as defined above in an amount effective in the treatment of said disorders, and a pharmaceutically acceptable carrier. More specific and most preferred compositions for the treatment of such illnesses and disorders comprise a more specific and most preferred compound of formula I as defined above.
The invention further includes a method for the treatment of illnesses induced or facilitated by corticotropin releasing factor by administering to a subject in need of such treatment a compound of formula I or the known compound, both as defined above, and a method for the treatment of stress and anxiety related disorders, including stress-induced depression and headache, abdominal bowel syndrome, inflammatory disorders, immune suppression, HIV infections, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems, particularly depression, by administering to a subject in need of such treatment a compound of formula I as well as the known compound, both as defined above. More specific and most preferred methods for the treatment of such illnesses and disorders comprise a more specific and most preferred compound of formula I as described above.
Whenever reference is made herein to C1-C6 alkyl, a straight or branched chain alkyl of one to six carbon atoms is meant, such as methyl, ethyl, isopropyl or hexyl.
Whenever reference is made herein to C1-C6 alkyl, in the definition of R5 and R1, this includes unsaturated C2-C6 alkyl, such as C2-C6 alkyl having one double or triple bond, C3-C6 alkyl having two double bonds, and C4-C6 alkyl having two triple bonds.
Whenever reference is made hereafter to a compound of formula I, this includes the known compound of formula I as described above.
Whenever R3 is a heterocyclic group, the attachment to A, defined above, is through one of the carbons in the heterocyclic group. Similarly, when R4 is a heterocyclic group, the attachment to the nitrogen in the pyrazole ring is through one of the carbons in the heterocyclic group.
Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl containing one to three of O, S or Nxe2x80x94Z, it is understood that the oxygen and sulfur ring atoms are not adjacent to each other.
The compounds of the formula I wherein R1 is amino or C1-C6 alkyl, and R2 is methylthio, having the formula II (not shown), may be prepared from a compound of the formula 
wherein R10 is cyano or C(O)(C1-C6 alkyl) and A and R3 are as defined above with reference to formula I, by reaction with a compound of the formula
R4xe2x80x94NHNH2xe2x80x83xe2x80x83IV
wherein R4 is as defined with reference to formula I. This reaction is generally carried out in a polar solvent, such as a C1-C6 alcohol. The reaction temperature generally ranges from about 20xc2x0 C. to about 160xc2x0 C., and is conveniently the reflux temperature of the reaction mixture.
The compounds of formula III may be prepared by treating a compound of the formula
R3xe2x80x94Axe2x80x94CH2R10xe2x80x83xe2x80x83V
with a base such as sodium hydride, in the presence of carbon disulfide followed by reaction of the formed intermediate with methyl iodide in a reaction solvent such as dimethylsulfoxide.
The compounds of formula IV are readily available or may be obtained by methods known in the art.
The compounds of formula V may be prepared by known methods.
The compounds of the formula I wherein R2 is alkoxy, amino, or mono- or disubstituted amino may be prepared by using the above procedure with R4NHNH2 from the corresponding compounds of the formula 
wherein A and R3 are as defined with reference to formula I, R10 is as defined with reference to formula III, and R, Rxe2x80x2 and Rxe2x80x3 are each hydrogen or C1-C6 alkyl in accordance with the definition of R2 above.
The compounds of the formula I wherein R1 is C1-C6 alkoxy or C1-C6 alkylthio and R2 is C1-C6 alkyl may be prepared from a compound of the formula 
wherein Rx is chloro or bromo, R2 is C1-C6 alkyl, and R3, R4 and A are as defined above with reference to formula I, with a C1-C6 alcohol or C1-C6 mercaptan in the presence of a base. The reaction is generally carried out in a polar solvent such as ethanol or t-butanol at temperatures from about 20xc2x0 C. to about 160xc2x0 C. and conveniently room temperature.
The compounds of the formula IX may be prepared by treating a compound of the formula 
with a halogenating agent such as thionlyl chloride or bromide, or phosphorous oxychloride or pentachloride, or phosphorous oxybromide or pentabromide. The reaction may be carried out without a solvent or in an aprotic solvent such as methylene chloride, or dichloroethane at temperatures of about 0xc2x0 C. to about 100xc2x0 C.
Compounds of formula X may be prepared by treating compounds of the formula 
with an activated derivative of a carboxylic or sulfonic acid of the formula R3AOH, such as an acid chloride of the formula R3ACl wherein R3 and A are as defined with reference to formula I, in the presence of calcium hydroxide in an aprotic solvent such as dioxane as described in Jensen, Acta Chem. Scand., 13, 1668-1670 (1959) at temperatures of from about 20xc2x0 C. to about 100xc2x0 C. Compounds of the formula XI are known in the art.
The compounds of the formula I wherein R1 is C1-C6 alkoxy or C1-C6 alkylthio and R2 is C1-C6 alkylthio may be prepared from a compound of the formula 
wherein RY is chloro or bromo and R3, R4 and A are as defined above with reference to formula I, with a C1-C6 alcohol or C1-C6 mercaptan in the presence of a base. The reaction is generally carried out in a polar organic solvent such as ethanol or t-butanol at temperatures from about 20xc2x0 C. to about 160xc2x0 C., conveniently room temperature.
The compounds of the formula XII may be prepared from a compound of the formula 
by reaction with a halogenating agent such as thionyl chloride or bromide, or phosphorous oxychloride or pentachloride, or phosphorous oxybromide or pentabromide. The reaction may be carried out with a solvent or in an aprotic solvent such as methylene chloride or dichloroethane at temperatures of about 0xc2x0 C. to about 100xc2x0 C.
The compounds of the formula XIII may be prepared by treating a compound of the formula 
with activated benzoic or sulfonic acid derivatives, conveniently an acid chloride, in the presence of calcium hydroxide in an aprotic solvent such as dioxane as described in the above reference by Jensen.
The compounds of the formula XIV may be prepared by treating a compound of the formula 
wherein Rz is chloro, bromo with a C1-C6 mercaptan in the presence of a base. The reaction is generally carried out in a polar organic solvent such as t-butanol at temperatures from about 20xc2x0 C. to about 160xc2x0 C., conveniently the reflux temperatures of the reaction mixture.
The compounds of the formula XV may be prepared from compounds of the formula 
with a halogenating agent such a thionyl chloride or bromide, or phosphorous oxychloride or pentachloride, or phosphorous oxybromide or pentabromide. The reaction may be carried out without a solvent or in an aprotic solvent such as methylene chloride or dichloroethane at temperatures of about 0xc2x0 C. to about 100xc2x0 C.
The compounds of the formula I wherein R1 is C1-C6 alkoxy or C1-C6 alkylthio and R2 is C1-C6 alkoxy may be prepared from a compound of the formula 
wherein RXX is chloro or bromo, R2 is C1-C6 alkoxy and R3, R4 and A are as defined above with reference to formula I, with a C1-C6 alcohol or C1-C6 mercaptan in the presence of a base. The reaction is generally carried out in a polar organic solvent such as ethanol or t-butanol at temperatures from about 20xc2x0 C. to about 160xc2x0 C., conveniently the reflux temperature of the reaction mixture.
The compounds of the formula XVII may be prepared from a compound of the formula 
by reaction with a halogenating agent such as thionyl chloride or bromide, or phosphorous oxychloride or pentachloride, or phosphorous oxybromide or pentabromide. The reaction may be carried out without a solvent or in an aprotic solvent such as methylene chloride, or dichloroethane at temperatures of about 0xc2x0 C. to about 100xc2x0 C.
The compounds of the formula XVIII may be prepared by treating a compound of the formula 
with an activated derivative of a carboxylic or sulfonic acid of the formula R3AOH, conveniently an acid chloride of the formula R3ACl wherein R3 and A are as defined above with reference to formula I, in the presence of calcium hydroxide in an aprotic solvent such a dioxane as described by Jensen in the reference cited above.
The compounds of the formula XIX may be prepared by treating a compound of the above formula XV with an alcohol in the presence of a base. The reaction is generally carried out in a polar organic solvent such as ethanol at temperatures from about 20xc2x0 C. to about 160xc2x0 C., conveniently the reflux temperatures of the reaction mixture.
The compounds of the formula I wherein R1 is amino and R2 is O(C1-C6alkyl) may be prepared by reacting a compound of the formula 
wherein R3, R4 and A are as defined above with reference to formula I, with hydrazine in a solvent such as a C1-C6 alcohol, conveniently at the boiling point of the solvent.
The compounds of the formula XX may be prepared by treating a compound of the formula 
wherein R3, R4 and A are as defined above with reference to formula I, with an alkylating agent such as di(C1-C6 alkyl) sulfate, and a base such as sodium hydride, in a solvent such as dimethylsulfoxide.
The compounds of the formula XXI may be prepared by treating a compound of the formula 
with an activated derivative of a carboxylic or sulfonic acid of the formula R3AOH such as an acid chloride of the formula R3ACl, wherein R3 and A are as defined with reference to formula I, in the presence of a Lewis acid such as aluminum chloride in an aprotic solvent such as methylene chloride, dichloroethane, or tetrachloroethane, at temperatures of about 0xc2x0 C. to about 150xc2x0 C.
The compounds of the formula XXII may be prepared by treatment of a compound of the formula 
with phthalic anhydride in acetic acid at the boiling point of the solvent.
The compounds of the formula XXIII may be prepared by contacting cyanoacetyl chloride with R4NHNH2 in the presence of a base followed by heating the resulting hydrazide at reflux in alcoholic solution in the presence of a base.
The compounds of formula I wherein A and R1 are taken together to form pyrimidinyl have the formula 
wherein R2, R3, R4, and R5 are as defined above with reference to formula I. These compounds may be prepared by cyclization of a compound of the above formula I wherein A is Cxe2x95x90O and R1 is amino with a compound of the formula 
wherein R5 is as defined with reference to formula I. This reaction is generally carried out at 100 to 250xc2x0 C., and conveniently at the reflux temperature of the compound XXV.
The compounds of formula I wherein A and R1 are taken together to form 5-pyridyl have the formula 
wherein R2, R3, R4 and R5 are as defined with reference to formula I. These compounds may be prepared as shown in Reaction Scheme 1. 
The compounds of formula XXIX are prepared by reacting a ketone of the formula XXVII with a compound of the formula XXVIII in a suitable solvent such as tetrahydrofurane in the presence of a base such as sodium hydride. The reaction is conveniently carried out at the reflux temperature of the reaction mixture.
The compound XXIX is reacted with a compound of the formula R2C(OCH3)3 to form the compound XXX. The reaction is carried out in a suitable solvent such as ethyl acetate, conveniently at the reflux temperature of the reaction mixture. The wavy line  in formula XXX indicates that either isomer of this compound is included, in accordance with accepted convention for indicating stereoisomers.
The compound XXXI is prepared by reacting compound XXX with a hydrazine of the formula H2NNHR4 wherein R4 is as defined with reference to formula I. The reaction is carried out in a suitable solvent such as ethanol, conveniently at the reflux temperature of the reaction mixture.
The compounds of formula XXVI wherein R5 is linked to position 6 is formed by first reacting compound XXXI with hydrazine hydrate in a suitable solvent such as ethanol, conveniently at the reflux temperature of the reaction mixture. The compound XXXII is separated from precipitated phthalhydrazide and taken up in an organic solvent such as toluene. The compound XXVI is formed by dehydrogenation of compound XXXII with palladium over carbon.
Reaction Scheme 1 shows the preparation of compounds XXVI wherein R5 is in the 6-position. A similar reaction sequence may be followed to prepare compounds XXVI wherein R5 is in the 7-position by replacing compound XXVIII by a compound of the formula 
The compounds of formula I wherein A is Cxe2x95x90O and R1 and R2 are the same group R7 may be prepared by reacting a xcex2-ketone of the formula 
with the hydrazine of the formula IV as defined above to form a pyrazole compound of the formula 
The reaction proceeds at reflux in an appropriate solvent such as ethanol. After bromination of the pyrazole compound, e.g. with bromine in acetic acid, to form the corresponding 4-bromo derivative and conventional metallation, e.g. with t-butyl lithium, at xe2x88x9278xc2x0 C. in tetrahydrofuran, a suitably activated R3 carboxylic acid such as the acid chloride R3C(O)Cl is added to give the desired compound I.
The compounds of formula I wherein A is Cxe2x95x90O and R1 and R2 are not the same, and wherein R1 or R2 is attached through a C2H4 fragment, may be prepared from a pyranone of the formula 
wherein R3 is as defined above, and R2 is as defined above when R11 is C3-C6 alkyl which may be substituted by 1 to 3 of R6, or R2 is R1 when R11 is C3-C6 alkyl which may be substituted by one to three of hydroxy, amino, carboxy, amido, NH(Cxe2x95x90O)(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), (Cxe2x95x90O)O(C1-C6), C1-C3 alkoxy, C1-C3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro. The compound XXXIV is reacted with a hydrazine of the formula H2NNHR4 wherein R4 is as defined above to form compounds of the formulae 
which on dehydration and hydrogenation result in compounds of the formulae 
The compounds of the formula I wherein A is Cxe2x95x90O and R2 is O(C1-C6 alkyl) may be prepared by reacting a hydrazine of the formula R4NHNH2 with a compound of the formula (A) in a suitable solvent 
such as THF or methylene chloride and cyclization of the resulting hydrazide with heat to give the intermediate (B). This compound may be reacted with an activated carboxyclic acid derivative such as the acid chloride R3(Cxe2x95x90O)Cl in the presence of a Lewis acid such as aluminum trichloride in a solvent such as ethylene dichloride at temperatures of from about xe2x88x9210xc2x0 C. to about 80xc2x0 C. The formed compound of formula I wherein R2 is hydroxy may be reacted with (C1-C6 alkyl)L wherein L is a leaving group such as chloro, bromo, or tosylate and C1-C6 alkyl may be substituted in accordance with the substituents in the definition of R2.
Those compounds of formula I wherein R1 is C1-C6 alkylamino or di(C1-C6 alkyl)amino may be prepared from corresponding compounds of formula I wherein R1 is amino. When R1 is methylamino or dimethylamino, reaction is with a methylating agent such as methyl iodide. When R1 is C2-C6 alkylamino or di(C2-C6 alkyl)amino, reaction is with an alkylating agent such as C2-C6 alkyl-L wherein L is a leaving group such as chloro, bromo, tosylate, or mesylate. Both the methylation and the C2-C6 alkylation is in the presence of a base such as sodium hydride and a solvent such as tetrahydrofuran, dimethyl formamide or dimethyl sulfoxide.
The acid addition salts are prepared in a conventional manner by treating a solution or suspension of the free base of formula I with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.
The compound of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions of the novel compound of formula I in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Additionally, it is possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes and ointments, in accordance with standard pharmaceutical practice.
The effective dosage for the compound of formula I depends on the intended route of administration and other factors such as age and weight of the patient, as generally known to a physician. The dosage also depends on the illness to be treated, although in general the daily dosage will range from about 0.1 to 50 mg/kg of the body weight of the patient. More specifically, the daily dosage for stress-induced illnesses will generally range from about 0.1 to 50 mg/kg of the body weight of the patient to be treated, for treatment of inflammatory diseases about 0.1 to about 100 mg/kg will be needed, for Alzheimer""s disease, about 0.1 to about 50 mg/kg, as well as for gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, and drug and alcohol withdrawal symptoms.
The methods for testing the compounds for formula I for their CRF antagonist activity are according to the procedures of Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985) which determine the binding activity of a test compound to a CRF receptor. The binding activity for the compounds of formula I generally ranges from about 0.2 nanomolar to about 10 micromolar.
The following abbreviations are used in the Examples: Ph=phenyl; iPr=isopropyl; HRMS=high resolution mass spectrum.